TY - JOUR
T1 - Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans
AU - Lessard, Christopher J.
AU - Sajuthi, Satria
AU - Zhao, Jian
AU - Kim, Kwangwoo
AU - Ice, John A.
AU - Li, He
AU - Ainsworth, Hannah
AU - Rasmussen, Astrid
AU - Kelly, Jennifer A.
AU - Marion, Miranda
AU - Bang, So Young
AU - Bin Joo, Young
AU - Choi, Jeongim
AU - Lee, Hye Soon
AU - Mo Kang, Young
AU - Suh, Chang Hee
AU - Tae Chung, Won
AU - Lee, Soo Kon
AU - Choe, Jung Yoon
AU - Cheol Shim, Seung
AU - Hee Oh, Ji
AU - Jin Kim, Young
AU - Han, Bok Ghee
AU - Shen, Nan
AU - Siew Howe, Hwee
AU - Wakeland, Edward K.
AU - Li, Quan Zhen
AU - Wook Song, Yeong
AU - Gaffney, Patrick M.
AU - Alarcón-Riquelme, Marta E.
AU - Criswell, Lindsey A.
AU - Jacob, Chaim O.
AU - Kimberly, Robert P.
AU - Vyse, Timothy J.
AU - Harley, John B.
AU - Sivils, Kathy L.
AU - Bae, Sang Cheol
AU - Langefeld, Carl D.
AU - Tsao, Betty P.
N1 - Publisher Copyright:
© 2016, American College of Rheumatology.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Objective Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. Methods A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. Results Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10-8). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10-8, odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10-11; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1∗1501 and HLA-DQB1∗0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. Conclusion Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.
AB - Objective Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. Methods A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. Results Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10-8). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10-8, odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10-11; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1∗1501 and HLA-DQB1∗0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. Conclusion Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.
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U2 - 10.1002/art.39548
DO - 10.1002/art.39548
M3 - Article
C2 - 26663301
AN - SCOPUS:84964600746
SN - 2326-5191
VL - 68
SP - 1197
EP - 1209
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 5
ER -